Metabolic syndrome is a comprehensive manifestation that refers to syndrome involving health risk factors such as hypertriglyceridemia, hypertension, glycometabolism disorder, blood coagulation disorder and obesity. Metabolic syndrome itself is not fatal, but indicates a predisposition to severe diseases such as diabetes and ischemic cardiovascular diseases, and is understood as the most threatening diseases among modern people. Not long ago, Metabolic syndrome was known by various other names including Syndrome X, due to lack of knowledge about causes of such syndrome, but was officially designated as Metabolic Syndrome or Insulin Resistance Syndrome through Adult Treatment Program III (ATP III) enacted by the WHO and the National Heart, Lung, and Blood Institute of the NIH.
Insulin resistance refers to a phenomenon wherein, even though insulin is normally secreted in vivo, insulin does not induce sufficient supply of glucose to cells. Therefore, in case of person having insulin resistance, glucose in the blood is not absorbed into cells, thus causing hyperglycemia, thereby cells leading to the manifestation of metabolic syndrome which cannot perform normal functions due to a shortage of glucose.
At present, there are no drugs available for the treatment of metabolic syndrome. Attempts have been made to treat metabolic syndrome using therapeutic agents for diabetes, hyperlipidemia and hypertension, but these drugs have limited effectiveness in treating metabolic syndrome as the drug. As currently available drugs, metformin, drugs belonging to the TZD (thiazolidinediones) family, glucosidase inhibitors, dual PPARγ/α agonists and DDP (Dipeptidyl peptidase) IV inhibitors, which are used for the treatment of diabetes, have received a great deal of attention as promising drugs for treating metabolic syndrome. In addition, a great deal of interest has been directed to isoforms of apoA-I and related peptides thereof, which are targets of anti-blood pressure drugs and anti-hyperlipidemic drugs, and CETP (Cholesterol ester transport protein) inhibitors. These drugs which can treat with metabolic syndrome are known to show common effect that AMPK is activated. Among the drugs as referred above, metformin and TZD drugs are also belong to this class. For this reason, the present inventors have also employed a method of confirming the presence/absence of activation effects on AMP-activated protein kinase (AMPK), as the most fundamental primary test to confirm biological efficacy of compounds of interest on disease syndromes.
In this way, AMPK is known to play a central role in energy metabolism of glucose, protein and fat in vitro and in vivo. Neil, et al (Nature drug discovery, 3(Apr.), 340, 2004) has asserted that AMPK and Malonyl-CoA are possible targets for the treatment of metabolic syndromes, and they have also stated that patients suffering from metabolic syndromes can be characterized by insulin resistance, obesity, hypertension, dyslipidemia, and dysfunction of pancreatic beta cells, type II diabetes and manifestation of arteriosclerosis. It was hypothesized that a common feature linking these multiple abnormalities is dysregulation of AMPK/Malonyl-CoA energy level-sensing and signaling network. It was proposed that such dysregulation leads to alterations in cellular fatty-acid metabolism that in turn cause abnormal fat accumulation, cellular dysfunction and ultimately disease. Evidence is also presented that factors activating AMPK and/or reducing malonyl-CoA levels might reverse these abnormalities and syndromes or prevent incidence of these diseases.
Roger, et al (Cell, 117, 145-151, 2004) have suggested that AMPK may be a possible target to control obesity by lowering activity of hypothalamic AMPK, thereby increasing a content of malonyl-CoA and then regulating appetite for food intake.
Lee, et al (Nature medicine, 13(Jun.), 2004) have suggested that alpha-lipoic acid can exert anti-obesity effects by suppressing hypothalamic AMPK activity, thus controlling appetite. They have also reported that alpha-lipoic acid promotes fat metabolism via activation of AMPK in muscle tissues, not hypothalamus, and alpha-lipoic acid is therapeutically effective for the treatment of obesity because it facilitates energy expenditure by activating UCP-1, particularly in adipocytes.
Diraison, et al (Diabetes 53, S84-91, 2004) have reported that activation of AMPK in pancreatic cells leads to four-fold increases in expression of the gut hormone peptide YY responsible for appetite control and thus appetite can be regulated by the action of AMPK in other tissues other than hypothalamus.
Nandakumar, et al (Progress in lipid research 42, 238-256, 2003) have proposed that, in ischemic heart diseases, AMPK would be a target to treat ischemia reperfusion injuries via regulation of fat and glucose metabolism.
Min, et al (Am. J. Physiol. Gastrointest Liver Physiol 287, G1-6, 2004) have reported that AMPK is effective for regulation of alcoholic fatty liver.
Genevieve, et al (J. Biol. Chem. 279, 20767-74, 2004) have reported that activation of AMPK inhibits activity of an iNOS enzyme that is an inflammation mediator in chronic inflammatory conditions or endotoxin shock, including obesity-related diabetes and thus AMPK will be effective for developing new medicines having a mechanism capable of enhancing insulin sensitivity. In addition, they have reported that inhibition of iNOS activity is effected by activation of AMPK, and thus this finding is clinically applicable to diseases such as septicemia, multiple sclerosis, myocardial infarction, inflammatory bowel diseases and pancreatic beta-cell dysfunction.
Zing-ping et al (FEBS Letters 443, 285-289, 1999) have reported that AMPK activates endothelial NO synthase through phosphorylation, in the presence of Ca-calmodulin in murine muscle cells and myocardial cells. This represents that AMPK is implicated in heart diseases including angina pectoris.
Javier, et al (Genes & Develop. 2004) have reported that a lifespan can be extended by limiting utilization of energy and such a prolonged lifespan is achieved in a manner that an in vivo AMP/ATP ratio is increased and therefore the α2 subunit of AMPK is activated by AMP. Therefore, they have suggested that AMPK may function as a sensor to detect the relationship between lifespan extension and energy level and insulin-like signal information.
Meanwhile, Danshen (Salvia miltiorrhiza) has been widely used as an important herbal medicine in Northeast Asia regions since ancient times, and is well-known to have excellent effects on the prevention and treatment of various cardiovascular diseases. Upon focusing our attention to such therapeutic efficacy of Danshen, the inventors of the present invention have suggested that main ingredients of Danshen are superb medicinal substances capable of treating various diseases such as obesity, diabetes and metabolic syndromes. For example, see Korean Patent Nos. 2003-0099556, 2003-0099557, 2003-0099657, 2003-0099658, 2004-0036195, 2004-0036197 and 2004-0050200, assigned to the present applicant. In particular, the present inventors have revealed that main principles of Danshen including Cryptotanshinone, 15,16-Dihydrotanshinone can treat metabolic syndrome diseases.

The inventors of the present invention have newly confirmed that novel naphthoquinone-based compounds such as β-lapachone {7,8-dihydro-2,2-dimethyl-2H-naphtho(2,3-b)dihydropyran-7,8-dione}, dunnione {2,3,3-tirmethyl-2,3,4,5-tetrahydro-naphtho(2,3-b)dihydrofuran-6,7-dione}, α-dunnione {2,3,3-tirmethyl-2,3,4,5-tetrahydro-naphtho(2,3-b)dihydrofuran-6,7-dione}, nocardinone A, nocardinone B, lantalucratin A, lantalucratin B and lantalucratin C not only have chemical functional group which is the same as or similar to Cryptotanshinone and Dihydrotanshinon and the like, but also have pharmacological actions as therapeutic and prophylactic agents for disease involving metabolic syndrome.
That is, the present inventor has attempted to examine whether naphthoquinone-based compounds as disclosed in the present invention activate AMPK in cells and tissues. Then, in order to examine profoundly therapeutic effects of the compounds for disease syndromes diseases based on results thus obtained, the present inventor have examined therapeutic effects for the treatment and/or prevention of disease involving metabolic syndromes including obesity and diabetes through various experiments using OB mice, a animal model of obesity caused by decreased secretion of leptin.
